The goal of this 5-year project is to discover the specific mechanisms that underlie the attention and working memory deficits that are central features of schizophrenia. These impairments contribute to the functional disability of the disorder, are likely related to genetic risk for the illness, and are largely unaffected by antipsychotic treatment. This translational research program involves collaboration between a clinical research laboratory and a team of basic cognitive scientists with expertise in attention and working memory. Our approach is to use the concepts and methods of contemporary cognitive neuroscience to subdivide the constructs of attention and working memory into individual subcomponents so that specific, falsifiable hypotheses can be constructed. The proposal includes 4 interrelated specific aims. In Aim 1, we examine the hypothesis that the illness compromises the ability to use goals to control attention, leading to deficits in perception, working memory and response selection. In Aim 2, we examine the interactions of attention and working memory and examine how impairments in each impact the other system. In Aim 3, we test the hypothesis that the illness compromises the ability to rapidly form precise working memory representations, thereby degrading behavioral performance. In Aim 4, we address individual differences in working memory and attentional performance among patients in order to determine whether patients vary along a single severity of impairment continuum or instead, differ in kind. Behavioral and neurophysiological experimental paradigms were chosen for their ability to isolate specific attention and working memory processes, yielding large, distinctive patterns of results in normal subjects, thereby increasing the opportunity to observe specific, interpretable deficits in SC. These data will provide new insight into the cognitive/neural systems that are impaired in SC, potentially clarifying the nature of the phenotype, and provide new targets for pharmacological treatment. PUBLIC HEALTH RELEVANCE: Most patients with schizophrenia suffer from significant disability for most of their adult lives. Impairments in attention and working memory have been shown to play an important role in determining the extent of disability that patients experience. This research program is designed to increase understanding of the specific processes that are involved in these important areas of cognitive impairment.